Efficient delivery of pharmaceuticals to the back of the eye is one of the most significant unmet needs of visual health care. Recently, there have been significant advances in the field of ophthalmic pharmaceuticals, with the development of vascular endothelial growth factor (VEGF) antagonists capable of minimizing ocular neovascularization, corticosteroids that can combat macular edema, and others such as antioxidants and hypertensive drugs. However, conventional drug delivery modalities are extremely inefficient for delivering therapeutically relevant doses of these advanced pharmaceuticals to affected tissues in the back of the eye.
Delivery of drugs to the posterior chamber of the eye is made difficult by the isolated nature of the eye, which is separated from systemic circulation by blood ocular barriers, the blood retinal barrier (BRB) and blood aqueous barrier (BAB). Furthermore, the eye is a segmented structure with numerous barriers to delivery and effective clearance mechanisms that effectively eliminate pharmaceuticals that successfully reach the posterior chamber. The segmented eye is divided into anterior and posterior regions. The anterior chamber is composed of the cornea, ciliary body, aqueous humor and the lens, whereas the posterior segment contains the choroid, vitreous body, and the retina. Topically applied drugs enter the anterior chamber by crossing the cornea, or through the conjunctiva and sclera. Drugs can also enter the anterior chamber from the systemic circulation, but must cross the BAB. Drugs are cleared from the anterior chamber via aqueous turnover, or by re-absorption into systemic circulation. The half-life of a typical drug within the aqueous of the anterior chamber is roughly one hour. Drugs can be introduced into the posterior segment through systemic circulation by crossing the BRB, through non-corneal permeation into the uvea or by direct injection into the vitreous. Drug clearance from the posterior segment occurs through either the anterior or posterior route. The anterior route involves diffusion across the vitreous and elimination via uveal blood flow and aqueous turnover, whereas elimination via the posterior route requires permeation through the BRB.
As a result of these numerous barriers, effective clearance routes and the segmented nature of the eye, delivery of drugs to the posterior segment is particularly challenging. Topically applied eye drops typically result in less than 5% uptake into the anterior chamber and negligible amounts enter the back of the eye. Systemically applied drugs are also severely limited in their ability to reach the back of the eye; only 1-2% of a systemically applied dose crosses the restrictive blood ocular barriers. Therefore, excessive systemic doses are required to achieve therapeutic concentrations of drug within the posterior segment of the eye. Furthermore, many new pharmaceuticals are protein-based and are therefore not suitable for oral delivery as they are rapidly denatured in the digestive system.
Direct injection into the vitreous cavity is a highly efficient technique to introduce therapeutically relevant doses of drug into the vitreous body and retinal tissues. However, due to the effective clearance mechanisms, frequent injections (every 4-6 weeks) are often required to maintain therapeutically relevant concentrations. While intravitreal injections are an acceptable means of delivery, frequent injections are associated with increased risk of complications such as endophthalmitis, cataract formation, vitreous hemorrhage, retinal detachment and patient discomfort.
In view of the foregoing, there is a need for drug delivery approaches that safely utilize the intravitreal route to provide localized delivery of therapeutics for sustained periods of time that do not require frequent perforation of the eye wall to deliver pharmaceuticals to the back of the eye to treat numerous debilitating ocular conditions.